1. Field of the Invention
The present invention describes a process for the preparation of methylphenidate hydrochloride. The process involves the esterification of ritalinic acid and methanol in the presence of an acid catalyst at a low temperature. The process may optionally involve the addition of an orthoester.
2. Related Art
Methylphenidate (MPD) and methylphenidate hydrochloride are therapeutic agents that are widely used for the treatment of children with attention-deficit hyperactivity disorder. Methylphenidate contains two chiral carbon atoms and thus, four isomers of methylphenidate are possible as shown in Scheme 1. Early formulations contained all four isomers, d-threo methylphenidate, l-threo methylphenidate, d-erythro methylphenidate, and l-erythro methylphenidate. Markowitz, J. S., et al., Pharmacotherapy 23:1281-1299 (2003). The erythro isomers were subsequently removed from the formulations due to their association with adverse effects.

Until the introduction of d-threo methylphenidate hydrochloride, (dexmethylphenidate hydrochloride, Focalin®) in 2002, all marketed forms of methylphenidate contained a 50:50 racemic mixture of d-threo methylphenidate and l-threo methylphenidate in the form of the hydrochloride salt (Ritalin®, Concerta®, Metadate®, and Methylin®). In 2007, a transdermal patch containing racemic dl-threo methylphenidate (Daytrana®) was approved by the FDA.
The attention-deficit hyperactivity disorder psychotherapeutic effects, as well as the undesired pressor and anorexic actions, reside primarily in the d-enantiomer. Eckerman, D. A., et al., Pharmacol. Biochem. Behav. 40:875-880 (1991). However, in view of the recent efforts to develop l-threo-methylphenidate as an antidepressant, the l-threo-methylphenidate isomer of racemic formulations may not necessarily represent a passive component. Rouhi, A. M., Chem. Eng. News 81:56-61 (2003).
Methylphenidate is metabolized primarily by de-esterification to the inactive metabolite ritalinic acid (RA). About 60-81% of the oral dose of dl-threo methylphenidate is excreted into the urine as the de-esterified metabolite, dl-threo ritalinic acid. Patrick, K. S., J. Med. Chem. 24:1237-1240 (1981).
Synthetic methods for preparing racemic mixtures of threo- and erythro-α-phenyl-2-piperidineacetamides as raw materials for the preparation of threo methylphenidate are described in U.S. Pat. Nos. 2,507,631; 2,838,519; 2,957,880; and 5,936,091; and in PCT International Patent Publication No. WO 01/27070. These methods include using sodium amide as base in the nucleophilic substitution of chlorine in 2-chloropyridine with phenylacetonitrile, followed by hydrolysis of the formed nitrile and reduction of the pyridine ring to a piperidine ring by hydrogenation on PtO2 catalyst to obtain erythro-enriched α-phenyl-2-piperidineacetamide, which is then subjected to epimerization, hydrolysis, and esterification of threo-ritalinic acid. Alternatively, 2-bromopyridine can be used instead of 2-chloropyridine. Deutsch, H. M., et al., J. Med. Chem. 39:1201-1209 (1996).
Several methods have been described in the literature for preparing the d-threo enantiomer of methylphenidate. An enzymatic resolution is described in U.S. Pat. No. 5,733,756. A recrystallization/crystallization method, as well as an enzymatic resolution, are disclosed in PCT International Patent Publication No. WO 98/25902.
U.S. Pat. No. 2,957,880 describes a sequence involving the resolution of the amide derivative of the corresponding erythro isomer, conversion to the threo isomer, followed by the hydrolysis of the amide to the corresponding acid, and esterification of the resulting acid with methanol. In U.S. Pat. No. 6,242,464, the d-threo enantiomer is prepared by resolving racemic threo methylphenidate employing a di-aroyltartaric acid, preferably a ditoluoyltartaric acid. In U.S. Pat. No. 6,121,453, the d-threo enantiomer is prepared by resolving racemic threo methylphenidate employing (−)-menthoxyacetic acid.
Prashad, M., et al., Tetrahedron: Asymmetry 9:2133-2136 (1998) describes the esterification of ritalinic acid in methanol with hydrogen chloride gas at 45-50° C. for 16 hours. Treatment of the free base with hydrogen chloride gas followed by crystallization afforded d-threo methylphenidate hydrochloride in 16% yield.
Prashad, M., et al., J. Org. Chem. 64:1750-1753 (1999) describes the esterification of tert-butyloxycarbonyl protected d-threo ritalinic acid in methanol with the addition of hydrogen chloride gas at 50° C. for 15 hours. From this reaction, d-threo methylphenidate hydrochloride was obtained in 70% yield.
U.S. Patent Application Publication No. 2005/0171155 describes the esterification of dl-ritalinic acid in about 20 molar equivalents of methanol saturated with hydrogen chloride gas under reflux. From the reaction, dl-threo methylphenidate hydrochloride was obtained in 37% yield.
U.S. Patent Application Publication No. 2006/0135777 describes the esterification of d-threo ritalinic acid hydrochloride with methanol by means of thionyl chloride in toluene and dimethylformamide as catalyst in a two-step exothermic process. The crude product was purified to afford the desired d-threo methylphenidate hydrochloride in 73% yield.
U.S. Patent Application Publication No. 2010/0179327 describes the preparation of amino acid esters such as methylphenidate. The reference describes the reaction of threo-α-phenyl-α-(2-piperidinyl)acetic acid, methanolic HCl, and trimethyl orthoacetate with heating at reflux (temperatures above 60° C.) to form methylphenidate. Conversion rates of 91.7 to 98.5% and yields of 42.2 to 95.0% are reported.
A need exists for a more practical and economical process for esterification of ritalinic acid to methylphenidate hydrochloride.